PROJECT SUMMARY This phased innovation application in response to RFA-MH-18-704 seeks support for an initial (R61) 2-year phase for milestone-driven testing of neural targets of intervention by a novel neurofeedback (NF) treatment. Using NF, we will target the neurocircuitry of affect regulation and self-processing in adolescents (ages 13-17) who have current significant suicide ideation and a recent suicide attempt. Attaining our proposed milestones would trigger support for three additional years (R33 phase) to confirm target engagement in a larger sample with random assignment to active NF intervention vs. Placebo NF, to assess the relationships between target engagement and changes in functional outcomes. Affect dysregulation and abnormal self-processing predict repeated suicide attempts in at risk populations. They are insufficiently addressed by medications or behavioral treatments. NF training elicits enduring improvements in those dimensions in prior Placebo controlled NF trials. To further develop this intervention, we seek to first identify the neural target best engaged by NF during a critical period for affect regulation and self-processing. Our pilot data and theoretical considerations support the overarching hypothesis that increased amygdala or dACC activity and their functional connectivity (FC) with the middle prefrontal cortex (mPFC) represent treatable targets via NF training. In the initial R61 phase we will estimate the effect size of intervention-related increases in dACC and amygdala activity and their FC with mPFC during self-processing and affect regulation task in 20 youth per loci with high-quality imaging and clinical data. The goal of this phase is to determine which loci is best up-regulated in adolescents and is associated with functional targets improvements. If we meet our proposed milestone that increased dACC or amygdala activity and their FC with the mPFC exceed a specific effect size and account for an appreciable proportion of the variance in affect regulation and self-processing behavior, we would proceed to the R33 phase. In the R33 phase, we will expand the study to test 70 adolescents randomized to active NF intervention (dACC or Amygdala) or to a placebo NF. For both phases, we will obtain state-of-the-art magnetic resonance imaging (MRI) data with a primary focus on functional MRI. Our specific aims in the R33 phase are to confirm target engagement in the groups randomized to active vs. the Placebo NF group; to examine the relationship between changes in the neural target and clinical improvements in affect regulation, self-processing and suicide ideation; and to identify mediators of improved functional outcomes. Evidence supporting the validity of dACC or amygdala circuits as a modifiable neural target would then support future studies to further enhance the effectiveness of neurofeedback in adolescents. Importantly, even negative results will be informative regarding the location and direction of neurofeedback (top=dACC vs. down=amygdala) that best attains substantial effects. Inconclusive results from brain imaging would still inform Bayesian priors for future studies of the neural substrates of affect regulation and self-processing impairments and their amelioration.